Use of cb1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability

ABSTRACT

Use of a CB1 receptor antagonist and/or inverse agonist, preferably rimonabant, for the preparation of drugs useful for increasing motor neuron excitability in the cerebral cortex and/or in the brain stem and/or at the spinal level, as well as a method for increasing motor neuron excitability through the administration of a CB1 antagonist/inverse agonist receptors, and to the use of a pharmaceutical composition which comprises a CB1 receptor antagonist and/or inverse agonist, preferably rimonabant, for increasing motor neuron excitability in the cerebral cortex and/or in the brain stem and/or at the spinal level.

This application is a national phase of PCT/ES2010/070012 filed on Jan.11, 2010 which claims priority to PCT/ES2009/000010 filed on Jan. 12,2009, the entire disclosures of all of which are incorporated byreference herein.

The invention relates to the use of a CB1 receptor antagonist and/orinverse agonist, preferably rimonabant, for the preparation of drugsuseful for increasing motor neuron excitability in the cerebral cortexand/or in the brain stem and/or at the spinal level, as well as a methodfor increasing motor neuron excitability through the administration of aCB1 receptor antagonist/inverse agonist, and to the use of apharmaceutical composition which comprises a CB1 receptor antagonistand/or inverse agonist, preferably rimonabant, for increasing motorneuron excitability in the cerebral cortex and/or in the brain stemand/or at the spinal level. Therefore, the present invention belongs tothe field of invention of medicine.

PRIOR ART

The endogenous cannabinoid system is formed by endogenous ligands, theirsynthesis and degradation enzymes and by two different specificreceptors cloned to date: cannabinoid receptor type 1 (CB1), andcannabinoid receptor type 2 (CB2). The agonists of the cannabinoidreceptor type 1 (CB1) may reduce spasticity and pain in a great numberof neurological, rheumatic, traumatic diseases and in cancer. Theagonism of the CB1 receptor also causes sleepiness.

Rimonabant is the inn (International nonproprietary name) forN-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.This compound was described for the first time in EP 656354 as a CB1receptor antagonist/inverse agonist. Rimonabant has passed severalclinical trials where it was proposed as a new alternative to treatobesity, achieving the marketing authorization of several medicineagencies including the European Medicines Agency (EMEA), and it wasmarketed in the European Union as ACOMPLIA®. With this indication,ACOMPLIA®, which comprises a dose of 20 mg/day of rimonabant, was usedas a supplement for diet and exercise in treating obese patients(defined as BMI+30 Kg/m² (BMI=body mass index)), or patients with BMI>27kilograms/m² which also have risk factors associated, such as type 2diabetes or dyslipidemia. Due to the continuous revisions medicalscience undergoes, the Committee for Medical Products of Human Use(CHMP) decided to restrict the use of the drug after July 2007. The CHMPrecommended a new updating of the use of Acomplia® in May 2008 and inOctober 2008, it concluded that the benefits of Acomplia® for thisindication did not compensate the risks observed and it decided tosuspend the marketing authorization of the drug for the whole of theEuropean Union (EU).

However, until now the capacity of Acomplia® for increasing motor neuronexcitability and its effects on fatigue had not been determined, whichextends the use of CB1 antagonists/inverse agonists as active componentsin the treatment of a large number of medical disorders.

Many neurological pathologies are characterized by a decrease incortical and spinal motor neuron excitability and more generally by adecrease in corticospinal motor output (for example, cerebralvasculopathies, spinal cord injury, chronic fatigue syndrome, etc). Itis also necessary to highlight that some diseases that are notcharacterized by a decrease in motor neuron excitability benefit from atemporary increase in motor neuron excitability and an increase incorticospinal motor output (for example, peripheral nerve pathologies,muscular hypotrophies, muscular fatigue, etc). In all these clinicalconditions, an increase in motor neuron excitability and consequentincrease in corticospinal output is beneficial. At present there are notreatments of proven efficacy for increasing motor neuron excitabilityand the consequent corticospinal output.

Many neurological pathologies are characterized by excessive sleepiness(hypersomnia, narcolepsy, chronic fatigue syndrome, Parkinson's disease.etc). In all these clinical conditions an increased activity of thearousal system is beneficial. At the present time there are fewtreatments of proven efficacy to activate the arousal system.

There are currently no treatments of proven efficacy for any of thedisease related to movement disorders that have symptoms that can bebeneficially treated by increasing the motor neuron excitability.

DESCRIPTION OF THE INVENTION

The present inventors have surprisingly found that CB1 receptorantagonists and/or inverse agonists increase motor neuron excitabilityin the cerebral cortex, the brain stem and at the spinal level in humanpatients. The present inventors have also surprisingly found that CB1receptor antagonists and/or inverse agonists increase the activity ofthe ascending activation system or arousal system. The present inventionalso discloses treatments for diseases related to a decrease in motorneuron excitability and/or the decrease in activation of the ascendingactivation system or arousal system, i.e. it relates to the use of theCB1 receptor antagonist and/or inverse agonist for the preparation of adrug for the treatment of diseases where the increase in motor neuronexcitability in the cerebral cortex, the brain stem and/or at the spinallevel is beneficial.

Therefore, the object of the present invention is the use of a CB1receptor antagonist and/or inverse agonist for the preparation of a drugfor the treatment of movement disorders, fatigue, the reduction ofexcessive daytime sleepiness, the reduction of bradykinesia and/or thereduction of hypokinesia.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the threshold values using transcranial magnetic andelectric stimulation before and after administration of 20 mg ofrimonabant. The threshold value is expressed in percentage (%) of themaximum stimulator output. The error bars represent the standarddeviations. In FIG. 1 the baseline values are shown in black and thevalues after rimonabant administration in white. The administration ofrimonabant significantly reduced the mean of the active motor thresholdusing transcranial magnetic stimulation, hereinafter called AMTtms(baseline 39±4% vs 35.5±4%; P=0.0008) whilst the resting motor thresholdvalue using transcranial magnetic stimulation, hereinafter called RMTwas not significantly affected (baseline 48±6% vs. 46.5±6% P=0.0775).

The administration of rimonabant significantly reduced the mean of theactive motor threshold using transcranial electric stimulation,hereinafter called AMTtes (baseline 19.6±6% vs 17.5±6%; P=0.0164).

FIG. 2 shows the amount of intracortical facilitation (ICF) before andafter administration of 20 mg of rimonabant. The ICF value is expressedin percentage (%) of the response obtained with the stimulation test inabsence of the conditioning stimulus. The error bars represent thestandard deviations. In FIG. 2 the baseline values are shown in blackand the values after rimonabant administration in white. Theadministration of rimonabant significantly increased the mean of ICF(baseline 117±21% vs+150±40%; P=0.0212).

FIG. 3 shows that the treatment of rats with CB1 receptorantagonists/inverse agonists (SR141716A in this example) decreasedlatency in the 24 hours after the injection, which means that inhibitionof this receptor increased resistance to fatigue during that time (FIG.3 a). This effect can clearly be observed in FIG. 3 b, which shows thatthe improvement in resistance to fatigue (decrease in latency) of therats treated with CB1 receptor antagonists/inverse agonists (SR141716Ain this example) was on average 75 seconds better in animals withSR141716A than in the animals treated with carrier 2 hours afterfatigue; and 125 seconds better in the animals with SR141716A than inthe animals treated with carrier 24 hours after fatigue. The X-axisindicates the time in hours (h) and the Y-axis indicates the Δ of thelatency in seconds (a) and the improvement in seconds with respect tothe carrier (b).

FIG. 4 shows that the treatment of rats with CB1 receptorantagonists/inverse agonists (AM281 in this example) decreased latencyin the 24 hours after injection, which means that the inhibition of thisreceptor increased resistance to fatigue during that time (FIG. 4 a).This effect can clearly be observed in FIG. 4 b, which shows that theimprovement in resistance to fatigue (decrease in latency) of the ratstreated with CB1 receptor antagonists/inverse agonists (AM281 in thisexample) was on average 185 seconds better in animals with AM281 than inthe animals treated with carrier 2 hours after fatigue; and 207 secondsbetter in the animals with AM281 than in the animals treated withcarrier 24 hours after fatigue. The X-axis indicates the time in hours(h) and the Y-axis indicates the Δ of the latency in seconds (a) and theimprovement in seconds with respect to the carrier (b).

FIG. 5 shows that CB1 receptor antagonists/inverse agonists increaseresistance in rats with moderate spinal cord injury subjected to forcedrun. As was observed for normal rats, the treatment of injured rats withrimonabant (SR141716A) decreased latency, i.e. it increased resistanceto fatigue 2 hours after the injection compared to the carriers (FIG. 5a). At the time of completing the fatigue test, 24 h later, theperformance of the carrier rats and SR141716A maintained the differencesobserved on the previous day (FIG. 5 a). This effect can be clearlyobserved in FIG. 5 b, which shows that the improvement in resistance tofatigue (decrease in latency) of the rats treated with CB1 receptorantagonists/inverse agonists (SR141716A in this example) was on average136 seconds better in the animals with SR141716A than in the animalstreated with carrier 2 hours after fatigue; and 200 seconds better inthe animals with SR141716A than in the animals treated with carrier 24hours after fatigue. The X-axis indicates the time in hours (h) and theY-axis indicates the Δ of the latency in seconds (a) and the improvementin seconds with respect to the carrier (b).

DETAILED DESCRIPTION OF THE INVENTION

The surprising effect of CB1 receptor antagonists and/or inverseagonists of increasing motor neuron excitability at the cortical leveland/or in the brain stem and/or at the spinal level can be used to treatdiseases or pathologies related to movement disorders and/or therecovery of motor function in central nervous system diseasescharacterized by motor dysfunction, such as strokes, multiple sclerosisor spinal cord lesion. All these pathologies are characterized by havinga decrease in corticospinal motor output and/or a decrease in motorneuron excitability (Ward, Curr Opin Neurol. 2004 December, 17(6),725-30, Thickbroom et al., J. Neurol. 2006 August, 253(8), 1048-53). Forthis reason, an increase in corticospinal motor output and/or increasein motor neuron excitability is beneficial. The effect of increasingmotor neuron excitability at the cortical level, in the brain stemand/or at the spinal level may be accompanied by exercise orrehabilitation to encourage motor recovery. In a particular embodimentthe movement disorder related to the central nervous system is strokes,in another embodiment it is multiple sclerosis, and a third embodimentit relates to use for the treatment of spinal cord lesions.

The use of CB1 receptor antagonists and/or inverse agonists is notlimited to movement disorders of the central nervous system, but theyare also useful for the treatment of movement disorders related to theperipheral nervous system, such as, for example, peripheral paralysis.The rehabilitation of these nerve lesions benefits from greateractivation of the altered nerve (see Grasso et al., Clin Ter. 1997September, 148(9), 351-92). An increase in motor neuron excitabilityproduces a greater activation of the nerve and, therefore, isbeneficial.

When motor neuron excitability is increased at the cortical level, inthe brain stem and/or at the spinal level, it may allow or improve therecovery of motor function in those diseases characterized by motordysfunction caused by disorders of the peripheral nervous system, suchas neuropathies of the cranial nerves (e.g. facial) and spinal nerve(e.g. Bell's palsy, Guillain-Barré syndrome, motor and sensorial-motorneuropathies). The effect of increasing motor neuron excitability at thecortical level, in the brain stem and/or at the spinal level may beaccompanied with exercise or rehabilitation to encourage motor recovery.The rehabilitation of these nerve lesions benefits from greateractivation of the altered nerve (see Grasso et al., Clin Ter. 1997September, 148(9), 351-92). An increase in motor neuron excitabilityproduces a greater activation of the nerve and, therefore, isbeneficial.

In a preferred embodiment, said disease of the peripheral nervous systemis motor neuropathy of the cranial and spinal nerves.

In another preferred embodiment, said disease of the peripheral nervoussystem is Bell's palsy.

In a preferred embodiment, said disease of the peripheral nervous systemis Guillain-Barré syndrome.

Fatigue is a decrease in the capacity to voluntarily produce maximummuscular force. Fatigue occurs in numerous parts of the motor pathway,including motor neurons, motor cortex and the spinal cord. Fatigue iscaused by different central and peripheral nervous mechanisms. Fatigueis characterized by a decrease in cortical and spinal motor neuronexcitability (Thickbroom et al., J. Neurol. 2006 August, 253(8),1048-53; Gandevia, Physiol Rev. 2001 October, 81(4), 1725-89) and by thedecrease in cortical motor output (Gandevia, Physiol Rev. 2001 October,81(4), 1725-89). An increase in motor neuron excitability and theconsequent increase in cortical motor output are beneficial. The presentinventors have found that the CB1 receptor antagonists and/or inverseagonist reduce the feeling of fatigue, in particular of fatigueassociated to strokes, multiple sclerosis and/or chronic fatiguesyndrome. In a preferred embodiment said disease characterized byexcessive fatigue is strokes. In another preferred embodiment saiddisease characterized by excessive fatigue is multiple sclerosis. And inanother preferred embodiment said disease characterized by excessivefatigue is chronic fatigue syndrome.

Another particular embodiment relates to the use of CB1 receptorantagonists and/or inverse agonists for the treatment of motor neurondysfunction.

The increase in motor neuron excitability at the cortical level, in thebrain stem and/or at the spinal level can be used to temporarily improvefunction in motor neuron disorders such as amyotrophic lateral sclerosisand primary lateral sclerosis. In a preferred embodiment said disease isamyotrophic lateral sclerosis. In a preferred embodiment said disease isprimary lateral sclerosis.

The increase in activity of the arousal systems can be used to reduceexcessive daytime sleepiness which leads to narcolepsy and sleepdisorders characterized by hypersomnia. Narcolepsy is characterized by areduction in cortical excitability (Oliviero et al., J. Neurol. January2005, 252 (1), 56-61) whereby the increase in this excitability leads toa reduction thereof. The possibility of increasing the activity of thearousal systems is beneficial for excessive daytime sleepiness andhypersomnia associated to a decrease in the activity of the arousalsystems and which is also present with a decrease in cortical motorneuron excitability (By Gennaro et al., Neuroimage. 2007 Jul. 15, 36(4),1277-87).

The increase in motor neuron excitability at the cortical level, in thebrain stem and/or at the spinal level, can be used for the treatment ofbradykinesia and/or hypokinesia (e.g. Parkinson's disease andParkinsonisms). The symptoms of Parkinson's disease and Parkinsonismsimprove when, using non-pharmacological neuromodulation techniques, theexcitability of the cerebral cortex is increased (see Wu et al.,Neurotherapeutics. 2008 April, 5(2), 345-61). An increase in motorneuron excitability, and the consequent increase in cortical motoroutput, is beneficial in Parkinson's disease and in Parkinsonisms.

An additional particular object of the invention is a method to improvenormal motor function and/or accelerating recovery after a lesion of anyorigin (vascular, inflammatory, traumatic, etc.) of the central nervoussystem and/or peripheral nervous system and/or muscular system. Therehabilitation of these nervous lesions benefits from greater activationof the altered motor functions (see Grasso et al., Clin Ter. 1997September, 148(9), 351-92). An increase in motor neuron excitabilityproduces greater functional activation of the motor function and,therefore, may be beneficial. Another object of the present invention isthe use of a composition which comprises a CB1 receptor antagonistand/or inverse agonist to improve training in athletes. The training ofathletes benefits from a greater activation of the motor functions, forwhich reason the increase in motor neuron excitability is beneficial asit produces greater motor activation (see Lehmann et al., J Sports MedPhys Fitness. 1997 March, 37(1), 7-17).

The advantages of the present invention are associated to thecannabinoid receptors present at the cortical level and/or in the brainstem and/or at the spinal level, for which reason the surprising effectsof the present invention are applicable to all CB1 antagonists and/orinverse agonists. The term “CB1 antagonist” designates an antagonist ofthe cannabinoid CB1 receptor. This is a compound which bonds to thereceptor and lacks substantial capacity to activate the receptor ofsame. An antagonist prevents or reduces functional activation or theoccupation of the receptor by an agonist, such as anandamide. In someembodiments, the antagonist has an IC₅₀ of around 1 μM to around 1 nM.In other embodiments, the antagonist has an IC₅₀ of around 0.1 μM to0.01 μM, 1.0 μM M to 0.1 μM, or to 0.01 per μM to 1 nm. In someembodiments, the antagonist competes with the agonist in bonding to ashared bonding site in the receptor. These compounds are very well knownand highly defined in the state of the art. For example, U.S. Pat. No.5,747,524 and U.S. Pat. No. 6,017,919 disclose some of the valid methodsfor screening activity to CB1, which makes it possible to identify thecompounds useful in the invention.

In the classic activation model of G-protein coupled receptors, theclassic two-stage model, the agonist ligands stabilize or increase thefraction of active receptor, so that it can interact and activate aG-protein signal transducer and subsequent effectors. The ligands calledinverse agonists stabilize or increase the fraction of inactivereceptor, whilst the neutral antagonists do not alter the balancebetween the active or inactive states of the receptor. The firstgeneration of cannabinoid receptor antagonists developed in the 1990s,such as, for example SR141716A, a selective ligand for CB1(Rinaldi-Carmona et al., FEBS Lett. 1994 Aug. 22; 350(2-3):240-4),LY320135 or molecules designed by Alexandros Makriyannis: AM251 andAM281 which are analogues to SR141716A, produce opposite effects tothose of CB1 agonists. These inverse cannabinomimetic effects occur inthe absence of endogenous cannabinoids, which suggested that thecannabinoid CB1 receptors could exist in a state of constitutiveactivation in the absence of an agonist ligand, so that the inverseagonists displace the active state of the receptor to an inactive state.The inverse agonists produce opposite effects to those of the agonistsin some of the receptor bioassays. For example, “in vivo” the inverseagonism includes the signs of hyperalgia in inflammatory or neuropathicpain models (formalin test), carrageenan-induced paw oedema, thestimulation of intestinal motility, or the suppression of foodconsumption, whilst “in vitro” it produces an increase inneurotransmitter release (acetylcholine, noradrenaline or gammaaminobutyric) or inhibition of the bonding of [³⁵S]GTPγS in membranepreparations (see Pertwee R G in International Journal of Obesity 2006,30, S13-S18)

A first group of cannabinoid CB1 receptor antagonists are pyrazolederivatives. Patents EP 576357 and EP 658546 disclose examples ofpyrazole derivatives with affinity for the cannabinoid receptors. Moreparticularly, patent EP 656354 shows examples of pyrazole derivativesand discloses the compoundN-piperidin-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide,or SR 141716, and its pharmaceutically acceptable salts, which have goodaffinity for central cannabinoid receptors.

Another additional example of CB1 receptor antagonist is shown in U.S.Pat. No. 5,596,106, which discloses the compounds arylbenzo[b]thiopheneand benzo[b]furane as inhibitors or blockers of cannabinoid receptors inmammals.

Preferably, the cannabinoid antagonist is selective of the CB1 receptorand has a IC₅₀ with respect to the CB1 receptor which is a fourth partor less than the IC₅₀ for the CB2 receptor, or more preferably a tenthpart or less of the IC₅₀ of the CB2 receptor, and even more preferably aone hundredth part of the IC₅₀ of CB2 receptors.

Each of the aforementioned references is included for reference in itstotality.

Another representative example is iodopravadoline (AM-630). AM-630 is aCB1 receptor antagonist, but sometimes behaves as weak partial agonist(Hosohata, K.; Quock, R. M.; Hosohata, Y.; Burkey, T. H.; Makriyannis,A.; Consroe, P.; Roeske, W. R.; Yamamura, H. I. Life Sc. 1997, 61,PL115). More recently, the researchers of Eli Lilly describedaryl-aroyls substituting benzofuranes as CB1 receptor antagonists (e.g.LY-320135) (Felder, C. C.; Joyce, K. E.; Briley, E. J.; Glass, M.;Mackie, K. P.; Fahey, K. J.; Cullinan, G. J.; Hunden, D. C.; Johnson, D.W.; Chaney, M. O.; Koppel, G. A.; Brownstein, M. J. Pharmacol. Exp.Ther. 1998, 284, 291). Recently,3-alkyl-(5,5′-diphenyl)imidazolidinediones were described as ligands ofcannabinoid receptors which indicated that they were cannabinoidreceptor antagonists (Kanyonyo, M., Govaerts, S. J.; Hermans, E.;Poupaert, J. H., Lambert, D. M. Biorg. Med. Chem. Lett. 1999, 9, 2233).

Surprisingly, many CB1 receptor antagonists have been described withbehaviour of inverse agonists in vitro (Landsman, R. S.; Burkey, T. H.;Consroe, P.; Roeske, W. R.; Yamamura, H. I. Eur. J. Pharmacol. 1997,334, R1). Recent reviews provide a good description of the current stateof the art in the area of research into cannabinoids (Mechoulam, R.;Hanus, L.; Fride, E. Prog. Med. Chem. 1998, 35, 199. Lambert, b. M.Curr. Med. Chem. 1999, 6, 635. Mechoulam, R.; Fride, E.; Di Marzo, V.Eur. J. Pharmacol. 1998, 359, 1).

WO 01/70700 discloses the potent and selective antagonist activity onCB1 receptors of 4,5-dihydro-1H-pyrazole compounds.

The compounds of the following formula are also useful as cannabinoidCB1 receptors:

Where the substituents R₁, R₂, R₃, R₄, and R₅ are defined in U.S. Pat.No. 5,596,106 which is incorporated for reference in its totality. Thisreference discloses additional examples of derivatives ofaryl-benzo[b]thiophenes and arylbenzo[b]furanes and their use inaccordance with the present invention.

The cannabinoid antagonists with the following formula are particularlyuseful in accordance with the present invention.

Where R₁ is hydrogen, a fluoride, a hydroxyl, a (C₁-C₅)alkoxy, a(C₁-C₅)thioalkyl, a hydroxyl(C₁-C₅)alkoxy, a —NR₁₀R₁₁ group, a cyano, a(C₁-C₅)alkylsulfonyl or a (C₁-C₅) alkylsulfinyl; R₂ and R₃ areindependently a (C₁-C₄)alkyl or, they form a heterocyclic radical of 5to 10 members together with nitrogen whereto they are bonded which isnot substituted or which is monosubstituted or polysubstituted by a(C₁-C₃)alkyl or by a (C₁-C₃)alkoxy; R₄, R₅, R₆, R₇, R₈ and R₉ areindependently hydrogen, halogen or trifluoromethyl, and if R₁ is afluoride, R₄, R₅, R₆, R₇, R₈ and/or R₉ can also be a fluoromethyl, withthe condition that at least one of the R₄ or R₇ substituents is anothersubstituent that is not hydrogen; and R₁₀ and R₁₁ are independentlyhydrogen or a (C₁-C₅)alkyl, or R₁₀ and R₁₁, together with nitrogenwhereto they are bonded form a heterocyclic radical selected from amongpyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl and piperazine-1-yl,which are or are not substituted by a (C₁-C₄)alkyl, and its salts andsolvates.

Other selective examples of CB1 antagonist compounds are useful in thecontext of the present invention including (but not being limited to):

1) Analogue diarylpyrazoles described by Sanofi as selective CB1antagonists, as a representative example are the compounds SR-141716A,SR-147778, SR-140098, rimonabant and related compounds disclosed inpatents EP 0969835 and EP 1150961 (Central mediation of the cannabinoidcue: activity of a selective CB1 antagonist, SR 141716A Perio A,Rinaldi-Carmona M, Maruani J Behavioural Pharmacology 1996, 7:1(65-71)); WIN-54461 described by Sanofi-Winthrop (Cannabinoid receptorligands: Clinical and neuropharmacological considerations relevant tofuture drug discovery and development. Pertwee R G, Expert Opinion onInvestigational Drugs 1996, 5:10 (1245-1253)).

N-piperidin-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide(SR 141616, CAS number: 168273-06-1), and its pharmaceuticallyacceptable salts and its solvates have been usefully described in thepreparation of drugs for the treatment of appetite disorders.

SR 141716, (inn: rimonabant) is represented by the formula:

Rimonabant is especially described in patent EP 656354 or in the articleby M. Rinaldi-Carmona et al. (FEBS Lett., 1994, 350, 240-244). PatentEP1446384 A1 discloses new rimonabant derivatives, the formulation whichcomprises rimonabant is disclosed in WO2003082256, and the use ofrimonabant in appetite disorders is disclosed in patent WO99/00119.

2) Aminoalkylindoles have been described as CB1 receptor antagonists. Arepresentative example is the compound Iodopravadoline (AM-630).

3) Aryl-aroyl substitute the benzofuranes described by Eli Lilly asselective CB1 antagonists receptors, e.g. LY-320135 (Cannabinoidreceptor ligands: Clinical and neuropharmacological considerationsrelevant to future drug discovery and development. Pertwee R G, ExpertOpinion on Investigational Drugs 1996, 5:10-(1245-1253)).

4) The compounds described by Merck & Co, e.g. AM 251 and AM 281(Conference: 31st Annual Meeting of the Society for Neuroscience, SanDiego, USA, 10-15, November 2001), and the substituted imidazolylderivatives described in, e.g. US 2003114495 or WO 03/007887.

5) The azetidine derivatives described by Aventis Pharma, for example,in patent WO 02/28346 or in EP 1328269.

6) CP-55940 from Pfizer Inc. (Comparison of the pharmacology and signaltransduction of the human cannabinoid CB1 and CB2 receptors, Felder C C,Joyce K E, Briley E M, Mansouri J, Mackie K, Blond O, Lai Y, Ma A L,Mitchell R L, Molecular Pharmacology 1995, 48, 3 (443)).

7) The diaryl-pyrazine-amide derivatives from Astra Zeneca described,for example, in patent WO 03/051851.

8) ACPA and ACEA from Med. Coll. Wisconsin (Univ. Aberdeen), (“Effectsof AM 251 & AM 281, cannabinoid CB1 antagonists, on palatable foodintake in lewis rats” J. Pharmacol. Exp. Ther. 289, No 3,1427-33, 1999).

9) The pyrazole derivatives described by the University of Connecticute.g. in patent WO 01/29007.

10) HU-210 (International Association for the Study of Pain-Ninth WorldCongress (Part II) Vienna, Austria, Dickenson A H, Carpenter K, SuzukiR, IDDB MEETING REPORT 1999, Aug. 22-27) and HU-243 (Cannabinoidreceptor agonists and antagonists, Barth F, Current Opinion inTherapeutic Patents 1998, 8, 3 (301-313)) from the Yissum R&D Co HebrewUniv. of Jerusalem.

11) O-823 from Organix Inc. (Drug development pipeline: O-585, O-823,O-689, O-1072, monamines, Orgaix, Altropane Organix Inc, CompanyCommunication 1999, Aug. 10; IDDb database) and O-2093 from theConsiglio Nazionale delle Ricerche (“A structure/activity relationshipstudy on arvanil, endocannabinoid and vanilloid hybrid.”, Marzo D V,Griffin G, Petrocellis L, Brandi I, Bisogno T, Journal of Pharmacologyand Experimental Therapeutics 2002, 300, 3 (984-991)).

12) The 3-alkyl-(5,5′-diphenyl)imidazolidinediones described ascannabinoid receptor ligands.

13) The CB1 antagonist compounds currently under development by Bayer AG(IDDb database: company communication 2002, Feb. 28).

14) The CB1 antagonist pyrazole derivatives in accordance with formula(I) of U.S. Pat. No. 6,028,084 incorporated for reference in itstotality.

15) U.S. Pat. No. 6,017,919 discloses another appropriate group ofcannabinoid receptor antagonists and their use in accordance with thepresent invention, with general formula:

Where the substituents are defined in U.S. Pat. No. 6,017,919 which isincorporated for reference in its totality.

16) The antagonist activity in CB1 receptors of 4,5, dihydro-1H-pyrazolederivatives was shown in U.S. Pat. No. 5,747,524 and in US 2001/0053788A1, published on 20 Dec. 2001.

17) The 4,5,dihydro-1H-pyrazole derivative with CB1 receptor antagonistactivity disclosed in patent US 2001/0053788A1 and particularlydescribed by formula (I) contained in the aforementioned patent,published on 20 Dec. 2001 and which is incorporated for reference in itstotality.

18) The CB1 receptor antagonists disclosed in patent WO 2005049615especially the compounds described in examples 1 to 8.

19) The CB1 receptor antagonists disclosed in patent application WO2005047285 especially the compounds described in examples 1 to 99.

20) The CB1 receptor antagonist(4R)-3-(4-chlorophenyl)-4,5-dihydro-N-methyl-4-phenyl-N′-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-pyrazole-1-carboximidamide(SLV 326-34th Neuroscience, Abs 1009.4, October 2004) developed bySolvay (WO 0170700 A1).

The CB1 receptor antagonists developed by Solvay are described in theexamples of the following patents: WO 2005040130 A1, WO 2005028456 A1,WO 2005020988 A1, WO 2004026301 A1, WO 2003078413 A1, WO 2003027076 A2,WO 2003026648 A1, WO 2003026647 A1, WO 2002076949 A1 and WO 0170700 A1.

Particularly preferred are the CB1 receptor antagonists selected fromthe group consisting of rimonabant, AM-630, AM251, AM281, LY-320135,HU-210, HU-243, O-823, O-2093, SLV 326 and SR147778, preferablyrimonabant, AM251 or SR147778, more preferably rimonabant; and accordingto the case its pharmaceutically acceptable salts.

Below, some patient applications are listed wherein CB1 antagonistsand/or inverse agonists are disclosed: US 2008015228, US 2008015229, US2008058381, US 2008119653, US 2008200510, US 2008221078, US 2009005361,US 2009124643, US 2009215755, US 2009221692, US 2009281143 and US2009306037.

Some of the substances previously cited in scientific documents, patentsor by reference to other patents and their potential classes areconsidered potentially useful for the embodiments of the presentinvention, for which reason their content is fully incorporated in thepresent application for reference.

In another particular embodiment the CB1 receptor antagonist and/orinverse agonist comprises the following substructure and any of itstautomers and/or pharmaceutically acceptable salts:

With X and Y being independently selected from carbon and nitrogen.Especially preferred are the substructures that in the phenyl ring aresubstituted by at least one halogen group, preferably Cl, Br or I, andmore preferably in the para position.

Below, we list a series of particular CB1 receptor antagonists and/orinverse agonists useful for the present invention, whether in the formof free base or pharmaceutically acceptable salt:

The term “pharmaceutically acceptable salts” relates to a non-toxic saltof common use in the pharmaceutical industry which can be prepared inaccordance with methods well-known in the state of the art. Thepreferred salts for the compounds of the invention are those formed byHCl, HBr, HI, H2SO4, oxalic acid and benzoic acid.

The term “treatment” is understood to be the management and care of apatient in order to fight against the disease or disorder.

The compounds of the invention are administered at a therapeuticallyeffective dose. The term “therapeutically effective” relates to aquantity of a drug or therapeutic agent which causes the desiredbiological response of a tissue, a system or an animal (including man)which is being sought by a researcher or clinic.

The dose of CB1 antagonist and/or inverse agonist shall depend on thehealth of the subject treated, and the desired extension of thetreatment, the nature and the type of therapy, the frequency oftreatment and the nature of the effect desired. In general, the dose ofthe agent is in the range of around 0.001 to around 50 mg/kg in weightof patient per day, preferably expressed in daily dose per human patientbetween 1 and 2000 mg/day and even more preferably between 5 and 500 mg,administered in a single dose or divided. However, a certain variabilityin the dose range may also be necessary depending on the age, weight andtype of patient, also depending on the planned administration route andhow advanced it is and degree of severity of the disease or condition.

An indicative daily dose is in the range of between 1 and 500 mg,preferably from 1 to 100 mg of active agent, especially when it is fororal use. The dose can be administered in one go or in divided doses.Preferably, the CB1 antagonists and/or inverse agonists are administeredin the suitable form of unit dose, for example, a capsule or tablet, andwhich comprises a therapeutically effective dose, for example of around2 to around 200 mg. The active principle may be applied up to threetimes a day, preferably one or two times a day. The same recommendeddose is selected for the fixed combinations. The daily dose ofrimonabant required in the practice of the method of the presentinvention may vary depending on, for example, the form of administrationand the severity of the disease to be treated. A daily dose ofrimonabant is indicated in the range of between 1 to around 100 mg,preferably between 5 and 40 mg or 5 and 20 mg, of active agent of oraluse, appropriately administered in one go or in divided doses.Preferably rimonabant is administered in the form of pharmaceuticalcomposition comprising at least one pharmaceutically acceptableexcipient this oral composition preferably being in the form or oralsolid, such as, for example capsules or granules.

The administration of the effective quantity may be performed indifferent manners such as, for example, oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal and rectal administration. The most preferred form ofpharmaceutical composition is oral and solid, preferably in the form ofcapsules or tablets.

Preferably, the CB1 antagonist or inverse agonist is administered in theform of pharmaceutical composition which comprises between 1 and 2000 mgof CB1 receptor antagonist and/or inverse agonist and at least onepharmaceutically acceptable excipient or carrier, preferably between 5and 500 mg.

The term “pharmaceutically acceptable excipient” is understood to be anyingredient which does not have therapeutic activity and which are nottoxic and, therefore, are suitable as excipient. Suitable excipientsinclude the excipients of common use of pharmaceutical products such as,for example, microcrystalline cellulose, lactose, starch, magnesiumstearate, crosspovidone, povidone and talc.

EXAMPLES Example 1 Motor Neuron Excitability

The following experiments were performed using rimonabant, but it shouldbe understood that in no way should the scope of the present inventionbe limited to the example proposed below. In contrast, that tested forrimonabant can be extended to other CB1 antagonists or inverse agonists.

Rimonabant, a CB1 receptor antagonist, penetrates the hematoencephalicbarrier and it is well known that, at the doses normally used (20 mg perday), produces psychological effects in healthy human beings with a widerange of symptoms.

The objective of the present experiments was to use transcranialmagnetic and electric stimulation to test the effects of a single doseof 20 mg of rimonabant in motor cortex and spinal motor neuronexcitability.

A neurophysiological examination was carried out before and 24 hoursafter administration of a single dose of 20 mg of rimonabant.

Using transcranial magnetic stimulation (TMS) we evaluate theelectromyographic response thresholds in the first dorsal interosseous(FDI) at rest and during voluntary contraction. Using transcranialelectric stimulation (TES) we evaluate the electromyographic responsethresholds in the first dorsal interosseous during voluntarycontraction. Transcranial electric stimulation tends to activate theaxons of the corticospinal neurons in the white matter whilst magneticstimulation activates the same fibres trans-synaptically (Hallett, 2000Jul. 13, 406 (6792):147-50). Therefore, the response evoked electricallyare not as sensitive to changes in cortical excitability as those evokedby magnetic stimulation. We also evaluate short-latency intracorticalfacilitation (ICF). ICF was studied using the technique of Kujirai etal. (J. Physiol. 1993 November; 471:501-19).

Two magnetic stimuli were applied with the same stimulation coil, usinga Bistim module (Magstim Co., Whitland, UK) on the motor cortex and theeffect was studied of the first stimulus (conditioning factor) on thesecond stimulus (test). The conditioning stimulus was set at anintensity of 90% of the threshold under activation.

The intensity of the stimulus tests was adjusted to evoke a motor evokedpotential (MEP) at rest in the FDI with an amplitude of, approximately,1 mV from peak to peak. The programming of the conditioning stimulus wasaltered in relation to the test stimulus. The interstimulus intervals(ISIs) of 10, 15 and 25 ms were then investigated. Five stimuli wereapplied in each ISI.

The response facilitation conditional upon the three different ISIsstudied was then averaged to give a magnified average value. Theamplitude of the motor evoked potentials was expressed as percentages ofamplitude of the motor evoked potentials of the tests. The ICF is a formof facilitation of the corticospinal pathways which occurs at thecortical level.

Subjects

Nine healthy volunteers (average age±S.D 32.1±5.8 years) participated inthe experiments using TMS (transcranial magnetic stimulation) and sixparticipated in the experiments with electric stimulation. All subjectsgave their informed written consent. The study was developed inaccordance with the Declaration of Helsinki and approved by the LocalEthics Committee. The magnetic stimulation was developed using twoMagstim 200 high-power magnetic stimulators (Magstim Co., Whitland, UK)connected to the Bistim Module during all measurements. A figure of 8shaped coil was placed with an external diameter of 9 cm on the rightmotor cortex, in optimal position of the head to provoke a motorresponse in the contralateral first dorsal interosseous. The currentinduced a flow in the posteroanterior direction. The rest motorthreshold (RMT) was defined as the stimulus of minimum intensity capableof producing a motor evoked response at rest (of around 50 μV in 50% ofthe 10 attempts). The active motor threshold (AMTtms) was defined as thestimulus of minimum intensity capable of producing a motor evokedresponse (around 200 μV in 50% of the 10 attempts) during the isometriccontraction of the muscle tested at approximately 20% of the maximum. Aconstant voluntary contraction level was maintained by electromyogramdisplay oscilloscope placed in front of the subject.

In six subjects we also performed electric stimulation of the motorcortex during voluntary contraction. This was performed with a DigitimerD180A digital stimulator with a time constant of 50 μs. The cathode wasplaced in the vertex and the anode at 7 cm laterally (anodicstimulation). We evaluate the active electric motor threshold (AMTtes)defined as the stimulus of minimum intensity capable of producing amotor evoked response of around 200 μV in 50% of ten attempts during thevoluntary contraction. The effects of rimonabant on attention weremoderate and did not interfere with the capacity of subjects tocompletely comply with the experimental protocol requirements. Three ofthe subjects experienced agitation and anxiety (this effect lasted anaverage of 6 hours) and one suffered nauseas (during 24 h).

The RMT, the AMTtms and the AMTtes were compared before and after takingrimonabant using a paired t-test applying the Bonferroni correction(0.05/3=0.017). The ICF was compared before and after rimonabant using apaired t-test.

The administration of rimonabant significantly reduced the average ofAMTtms (baseline 39±4% vs 35.5±4%; P=0.0008) whilst the RMT was notaffected (baseline 48±6% vs 46.5±6% P=0.0775).

The administration of rimonabant significantly reduced the average ofAMTtes (baseline 19.6±6% vs 17.5±6%; P=0.0164). The administration ofrimonabant significantly increased the average of ICF (baseline 117±21%vs+150±40%; P=0.0212).

Rimonabant reduced AMTtms and AMTtes but did not have effects on therest motor threshold.

RMT and AMTtms reflect the excitability properties of the corticospinalneurons intrinsically and extrinsically modulated (Hallett, 2000). Atthe cortical level, AMTtms reflect the activity of a descending wave:the I1 wave (Di Lazzaro et al., Clin Neurophysiol. 1998, 109(5):397-401). But also a change in the excitability of the spinal motorneuron may affect the AMTtms. Basing ourselves on these considerations,we have demonstrated that the I1 waves or spinal cord motor neurons arefacilitated by the rimonabant CB1 antagonism/inverse agonism.

Transcranial electric stimulation tends to activate the axons of thecorticospinal neurons in the white matter whilst magnetic stimulationactivates the same fibres trans-synaptically (Hallett, 2000 Jul. 13, 406(6792):147-50). Therefore, the responses evoked electrically are not assensitive to changes in cortical excitability as those evoked bymagnetic stimulation.

Therefore, an effect similar to rimonabant in the electromyographicresponses evoked by magnetic and electric stimulation demonstrates thatthe increase in excitability takes place—perhaps not exclusively—in thespinal cord circuits. The present result provides the first evidencethat the excitability of the spinal motor circuits, verified bytranscranial magnetic and electric stimulation circuits, may beincreased by blocking CB1 receptors using rimonabant. However, it isdifficult to exclude a cortical role in the presence of changes inexcitability of the motor circuits at the spinal level only usingthreshold studies by transcranial stimulation.

Another important observation is that rimonabant increases intracorticalfacilitation. ICF occurs at the cortical level (Hallett, 2000 Jul. 13,406(6792): 147-50) for which reason we can conclude that the resultspresent provide the first evidence that cortical motor neuronexcitability may be increased in humans by blocking CB1 usingrimonabant.

Example 2 Fatigue

The objective of this study consisted of determining the effects ofcannabinoid CB1 receptor antagonists/inverse agonists(Rimonabant—SR141716A—, AM281) on fatigue in rats produced by a conveyerbelt.

Material and Methods

Animals. Male adult Wistar rats were used (300-350 g; 12 weeks old),obtained from Harlan-Interfauna Ibérica (Barcelona, Spain) kept in ouranimal house in a light:dark cycle of 12:12 hours, receiving food andwater ad libitum. The animals were handled in accordance with the guidespublished in the “NIH Guide for the Care and Use of Laboratory Animals”,the principles covered by the “Guidelines for the Use of Animals inNeuroscience Research” published by the American Neuroscience Society,and the European Union Guidelines (Directive 86/609/EEC). The rats wereassigned to the groups with injection of carrier or the CB1antagonists/inverse agonists (rimonabant (SR141716A) or AM281). Fiveuninjured animals and 3 injured animals were used for each group.

Forced run protocol using the conveyer belt and treatments.

The rats were acclimatized to the conveyer belt making them walk on thebelt at low speed. The forced run protocol consisted of a first sessionof 15 minutes run (20 m/min, 5% inclination) followed by a secondsession 2 hours later (Fatigue 2 h). The same protocol was repeated thefollowing day to study the continuance of the effects observed with thetreatment (Fatigue 24 h). In order to keep the rats running throughoutthe study, mild electric shock was used (20 mV, 1.67 Hz) and, possible,gentle touches by the experimenter's hand. The drugs were administeredimmediately after the first session of the first day. The treatmentsconsisted of a single intraperitoneal injection of SR141716A (0.25mg/Kg), or AM281 (0.25 mg/Kg), or carrier (2.5% Bovine Serum Albumin,SIGMA, Spain, in 0.9% NaCl).

Latency was defined as the number of seconds during the experiment wherethe animals touched the grille located at the end of the conveyer belt.The animals that remained more than twice at the electric grillereceiving discharges of over 10 seconds were considered exhausted andwere returned to their cages. In this case, latency time was alsoconsidered the remaining time until the end of the protocol. The latencyincrease (Δ latency) was calculated as the difference between the actionof the rat at each time minus the values of the first session.Therefore, the negative measurements reflect a decrease in latency, and,therefore, an improvement in motor capacity.

Results

The CB1 receptor antagonists/inverse agonists increase resistance inrats subjected to a forced run.

The treatment of rats with CB1 receptor antagonists/inverse agonists(SR141716A or AM281) decreased latency 2 hours after the injection,which means that the inhibition of this receptor increased resistance tofatigue in that time. On the following day, in the second measurement ofthe fatigue test, the rats treated with carrier performed the task in asimilar manner to the previous day whilst in the groups with CB1receptor antagonists/inverse agonists (SR141716A or AM281), not only wasthe improvement observed in the resistance maintained but it wasincreased above the levels of the previous day (FIGS. 3 a and 4 a). Thiseffect can clearly be observed in FIGS. 3 b and 4 b, showing theimprovement in resistance to fatigue (decrease in latency) of the ratstreated with CB1 receptor antagonists/inverse agonists (SR141716A,AM281) was on average 75 and 185 seconds better in animals withSR141716A or AM281 than in the carrier 2 hours after fatigue; and 125and 207 seconds better in animals with SR141716A or AM281 than in thecarrier 24 hours after fatigue.

Example 3 Moderate Spinal Cord Lesion

The objective of this study consisted of determining the effects ofcannabinoid CB1 receptor antagonists/inverse agonists(Rimonabant—SR141716A) in rats with moderate medullary lesion on thelocomotion and fatigue produced by conveyer belt.

Material and Methods

6 animals were subjected to a moderate spinal cord lesion by, using the“Infinite Horizon” motorized system (Precision Systems &Instrumentation, [PSI], Lexington, Ky.). The animals were anaesthetizedwith an intraperitoneal injection of pentobarbital sodium (45 mg/kg,Normon Veterinary Division, Madrid, Spain) and Xilagesic (2% Xylazine,10 mg/kg, Calier, Barcelona, Spain). When an absence of reflexes wereobserved, the rats were injected with a low dose of atropine (50 μg/kgof body weight; Brown Medical, Barcelona, Spain) to reduce salivary andbronchial secretion, and to avoid the presence of bradycardia and apossible cardiac arrest caused by surgery or by xylazine. Artificialtears were applied in the eyes to prevent corneal abrasion andinfection. After removing the spinal crest of the eighth thoracicvertebra, the spinal column of the animal was stabilized with clips andthe lesion was performed with a computer-controlled striker, which hitsthe surface of the spinal cord with a force of 150 Kdyn. After closingthe lesion site, the animals were hydrated and were placed in hotblankets during one hour. Post-operatory care included a subcutaneousinjection of Buprex (Buprenorphine, 0.05 mg/kg; Schering Plough, Madrid,Spain) and the prophylactic injection of antibiotic 1 hour after thelesion and on the following day (Baytril, Enrofloxacine, 1 mg/kg; Bayer,Kiel, Germany). The animals were fed with food for extruded rodents andthe bladder was manually emptied until autonomous control of theemptying was recovered. The hydration state was monitored as was thepresence of possible infections in the animals until the end of theexperiment. The experiments with conveyer belt were performed 7 daysafter the lesion.

Modified protocol for forced run on the conveyer belt for those injuredrats

As the spinal cord lesion produced clear deficits in the animals'locomotion, the fatigue protocol was modified to adapt it: Keeping thesame strategy of two sessions per day, we change the conveyer beltsettings, forcing the run more progressively and more prolonged. In thisway, the rats were subjected to a rate of 10 m/min during 10 minutes, 15m/min during 5 minutes, and, finally, 20 m/min during another 5 minutes(always with a 5° inclination). The drugs were administered as in theother non-injured groups.

Results

The CB1 receptor antagonists/inverse agonists increase resistance inrats with spinal cord lesion subjected to a forced run.

As was observed for normal rats, the treatment of injured rats withrimonabant decreased latency, i.e. it increased the resistance tofatigue 2 hours after the injection compared with the carriers (averageof 136 seconds difference in favour of the animals treated withSR141716A; FIG. 5). At the time of completing the fatigue test, 24 hlater, the performance of the carrier rats and SR141716A maintained thedifferences observed the previous day (average of 200 seconds differencein favour of the animals treated with SR141716A; FIG. 5).

1. A method for the treatment of fatigue, movement disorders, thereduction of excessive daytime sleepiness, the reduction ofbradykinesia, and/or the reduction of hypokinesia comprisingadministering to patient in need thereof an effective amount of a CB1receptor antagonist and/or inverse agonist.
 2. The method according toclaim 1, for the treatment of movement disorders.
 3. The methodaccording to claim 2, for the treatment of movement disorders related tothe central nervous system.
 4. The method according to claim 3, for thetreatment of stroke, multiple sclerosis and/or spinal cord lesions.5.-7. (canceled)
 8. The method according to claim 1, for the treatmentof movement disorders related to the peripheral nervous system. 9.-11.(canceled)
 12. The method according to claim 1, for the treatment offatigue. 13.-17. (canceled)
 18. The method according to claim 1, for thetreatment of motor neuron dysfunction, for the treatment of amyotrophiclateral sclerosis, and or for the treatment of primary lateralsclerosis.
 19. (canceled)
 20. The method according to claim 1, for thetreatment of excessive daytime sleepiness.
 21. (canceled)
 22. (canceled)23. The method according to claim 1, for the reduction of bradykinesiaand/or hypokinesia. 24.-26. (canceled)
 27. The method according to claim1, for the improvement of the normal motor function and/or acceleratingrecovery after a lesion of the central nervous system and/or peripheralnervous system and/or muscular system.
 28. The method according to claim1, characterized in that the CB1 receptor antagonist and/or inverseagonist comprises the following substructure and any of its tautomers:

with X and Y being independently selected from among carbon andnitrogen.
 29. (canceled)
 30. The method according to claim 28,characterized in that the CB1 receptor antagonist and/or inverse agonistcomprises a compound of the following formula, or any of its salts, inparticular hydrochloride:

31.-33. (canceled)
 34. The method according to claim 28, characterizedin that the CB1 receptor antagonist and/or inverse agonist is a compoundof the following formula:

or any of its pharmaceutically acceptable salts. 35.-40. (canceled) 41.The method according to claim 1, characterized in that the CB1 receptorantagonist and/or inverse agonist comprises rimonabant.
 42. (canceled)43. A method for improving training in athletes comprising theadministration of a CB1 receptor antagonist and/or inverse agonist. 44.(canceled)